REPRO: Sexual Differentiation and Disorders

Question 1

What is sexual determination?

Answer 1

It is a genetically controlled process dependant on the ‘switch’ on the Y chromosome. Chromosomal determination tells you if you’re male or female.

Question 2

What is sexual differentiation?

Answer 2

It is the process by which internal and external genitalia develop as male or female.

Question 3

What initiates male sexual differentiation?

Answer 3

Sex determining region (SRY) gene on short arm of Y chromosome, acting as a transcription factor

Question 4

What are the different levels of sexual differentiation, from embryo to adult?

Answer 4

• genotypic sex (if the embryo has XX or XY)
• gonadal sex (either ovaries or testes develop)
• phenotypic sex (outward appearance)
• legal sex (what’s written on the passport)
• gender identity (how you feel)

Question 5

Describe how the SRY gene is involved in gonadal development.

Answer 5

The SRY gene is a transcription factor that transcribes itself (positive feedback), along with a transcriptional cascade of events.

The presence of SRY causes the development of testis
The absence of SRY causes the development of ovaries

Question 6

What cells does testis develop and hormones produced?

Answer 6

The testis develops cells that make 2 important hormones:

• SERTOLI cells produce an anti-Mullerian hormone (AMH)
• LEYDIG cells make testosterone

Question 7

Describe gonadal development after fertilisation.

Answer 7

a bipotential cluster of cells in the embryo
-can develop either testis or ovaries (a pair of gonads) which are responsible for the differentiation of primordial germ cells into male/female gametes

Their precursor is derived from common somatic mesenchymal tissue precursors called the genital ridge primordia (3.5 to 4.5 weeks) on the posterior wall of the lower thoracic lumbar region.

Question 8

What are the three waves of cells that invade the genital ridge?

Answer 8

1. Primordial Germ Cells - become sperm (male) or oocytes (female)
2. Primitive Sex Cords - become Sertoli cells (male) or Granulosa cells (female)
3. Mesonephric Cells - become blood vessels and Leydig cells (male) or Theca cells (female)

Question 9

Describe primordial germ cell migration.

Answer 9

An initially small cluster of cells in the epithelium of the yolk sac expands by mitosis at around 3 weeks.
They then migrate to the connective tissue of the hindgut, to the region of the developing kidney and on to the genital ridge - completed by 6 weeks.

Question 10

Describe the formation of the sex cords (Sertoli/Granulosa).

Answer 10

In MALES:

1. There is SRY expression
2. The sex chords penetrate the medullary mesenchyme and surround the PGCs to form the testis chords.
3. They eventually become Sertoli cells, which express anti-Mullerian hormone (AMH).

In FEMALES:

1. There is no SRY expression.
2. The sex chords are ill-defined and do not penetrate deeply, but instead condense in the cortex as small clusters around PGCs.
3. They eventually become Granulosa cells.

Question 11

Describe the role of mesonephric cells in gonadal development.

Answer 11

originate in the mesonephric primordium

MALES, they act under the influence of pre-Sertoli cells to form:

• vascular tissue
• Leydig cells (synthesise testosterone, don’t express SRY)
• basement membrane - contributing to the formation of seminiferous tubules and rete-testis

In FEMALES, they form:

• vascular tissue
• Theca cells (synthesise androstenedione, which is a substrate for estradiol production by the granulosa)

Question 12

What are the two main structures involved in developing internal reproductive organs?

Answer 12

Mullerian ducts:

• Embryonic ducts that can develop into female internal genitalia
• inhibited in males by AMH

Wolffian ducts:

• Embryonic ducts that can develop into male internal genitalia under stimulation by testosterone
• lack of stimulation by testosterone means regression in female

Question 13

What is external genitalia development influenced by?

Answer 13

Testosterone and dihydrotestosterone (DHT)

Question 14

What is the role of 5-α-reductase in external differentiation?

Answer 14

an enzyme that converts testosterone into dihydrotestosterone
-in genital skin

It is present in both males and females, but because there is no substrate (testosterone) in females, its effects don’t play out.

Question 15

Male external differentiation

Answer 15

Conversion of testosterone to DHT by 5a Reductase:

• genital tubercle (initially clitoris) swells and becomes glans penis
• testes descend through the inguinal canal into the scrotum
• labia fuse, swell up and become ruggated to form the scrotum
• urethral fold folds around the urogenital membrane and becomes a tube
• the prostate forms

Question 16

Female external differentiation

Answer 16

5a Reductase present, but no testosterone, therefore no DHT produced, causing:

• genital tubercle becomes a clitoris
• genital swellings enlarge and form labia majora
• urethral fold develops in labia minora
• urogenital membranes forms the vestibule of the vagina

Question 17

List some disorders of sexual differentiation.

Answer 17

• gonadal dysgenesis: sexual differentiation is incomplete; also used as a general description of the abnormal development of the gonads
• sex reversal: phenotype not matching the genotype
• intersex: have some components of both tracts or have ambiguous genitalia

Question 18

What is it called when testosterone is being made in an XY individual, but it has no effect?
Cause?
What does that result in?

Answer 18

Androgen Insensitivity Syndrome (AIS).

caused by a mutation of the androgen receptor gene that renders tissues insensitive to androgenic hormones like testosterone.

• external female genitalia due to absence of DHT
• testis form due to SRY gene presence
• regressed internal genitalia because AMH inhibit Mullerian ducts and no testosterone stimulation for Wolffian duct differentiation

Question 19

What’s the difference between complete and partial AIS?

Answer 19

Complete AIS:

• appear female at birth, assigned the female gender despite being XY
• primary amenorrhoea, lack of body hair
• would be diagnosed by ultrasound scan and karyotype with male levels of androgens
• would never respond to androgen so they appear and feel female

Partial AIS:

• varying degrees of penile and scrotal development, from ambiguous genitalia to large clitoris
• surgery was universal, but now fortunately considered optional (at least best, delayed)
• decisions made on potential, very difficult for parents

Question 20

What is it called when testosterone is made in an XY individual, but not DHT?

What does that result in?

Answer 20

5-α-reductase Deficiency (autosomal recessive disorder so can depend on inter-related marriage.)

Testosterone in XY individuals can’t be converted to DHT:

• testes form due to SRY gene
• internal male genitalia due to AMH inhibiting Mullerian Ducts and stimulation of Wolffian Ducts by testosterone
• external female genitalia because no DHT no external male genitalia.

At puberty, high testosterone levels will occur at adrenarche and puberty may induce virilisation.

Question 21

Describe Turner Syndrome.

Answer 21

(XO)

• ovaries develop (no SRY gene)
• Internal female genitalia (no AMH for Mullerian duct development and lack of testosterone prevents Wolffian duct differentiation)
• external female genitalia

They have a failure of ovarian function. They have ]’streak’ ovaries, (ovarian dysgenesis-we need 2 X’s for proper ovarian development).

The uterus and tubes are present but small defects in growth and development may be present. There may be a need for steroid hormone support of the bones and uterus.

Question 22

What happens when an XX female is exposed to high levels of androgens in utero?

What does that result in?

Answer 22

Congenital Adrenal Hyperplasia (CAH) is the most common cause.

No SRY is expressed, so we don’t get any testes or AMH. The Mullerian ducts remain. The individual ends up with masculinised external genitalia, but the androgen levels are not usually high enough to rescue the Wolffian ducts.

Question 23

How would an XX female be exposed to high levels of androgens in utero?

Answer 23

Progestogens/steroid hormone precursors (in gonads) can be converted to cortisol and aldosterone (in adrenal glands) by 21a hydroxylase.

Defect/Deficiency in 21a hydroxylase causes:

• no cortisol/aldosterone was produced therefore more progestogens
• no negative feedback via HPA axis, increase in CRH and ACTH
• ACTH upregulates the P40scc enzyme to force more cholesterol into the steroid synthesis pathway
• progestogens converted to androgens (high testosterone)

Question 24

Describe the effects of Congenital Adrenal Hyperplasia (CAH).

Answer 24

If the enzyme is absent, then children may be wrongly gender assigned at birth, or may have ambiguous genitalia.

There needs to be a treatment with glucocorticoids to correct the feedback.

Also, in CAH, we need to be aware of the possibility of ‘salt washing due to the lack of aldosterone; this can be lethal.